Abstract
Introduction: Chromosome abnormalities and gene mutations are associated with distinct clinical features and outcome in AML patients (pts). Some of the most common recurrent aberrations are balanced translocations and inversions involving the 11q23/ MLL ( KMT2A ) locus. The objective of this study was to identify mutational patterns and outcome differences associated with distinct 11q23/ MLL rearrangements in AML.
Methods: Among 1592 adult pts with de novo AML treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols, and whose pretreatment karyotypes were centrally reviewed, we identified 85 (5%) pts with the most common 11q23/ MLL rearrangements [ i.e. , t(9;11)(p22;q23), n=36; t(6;11)(q27;q23), n=15; t(11;19)(q23;p13.1), n=14; t(11;19)(q23;p13.3), n=7; t/ins(10;11)(p12;q23), n=8; t(11;17)(q23;q21), n=5], who are subject of this study. There were 69 pts aged <60 years (y) and 16 aged ≥60y. Additional 11 pts had rare 11q23/ MLL rearrangements that were not included in subsequent analyses.
Mutational status of 79 cancer- and leukemia-associated genes was determined using a targeted next-generation sequencing panel, biallelic CEBPA was done using Sanger sequencing, and FLT3 -ITD was determined using fragment analysis in pretreatment bone marrow or blood samples containing ≥20% blasts. Genes were assigned to 9 previously described groups: chromatin remodeling, cohesin complex, kinases, methylation-related, NPM1 , RAS pathway, spliceosome, transcription factors, and tumor suppressors (Figure).
Younger pts who did not receive an allogeneic transplant in 1st complete remission (n=47) were analyzed for outcome.
Results: Overall, we detected 122 mutations in addition to the 11q23/ MLL rearrangements in 65 pts, while 20 pts did not have additional mutations in the analyzed genes. Among the 81 analyzed genes, 45 were mutated in ≥1 pts. Pts with 11q23/ MLL differed from 1496 AML pts without 11q23/ MLL rearrangements analyzed molecularly. For example, 11q23/ MLL pts had less additional mutations (median: 1 v 3 mutations per pt; range: 0-6 v 0-9; P<.001), never harbored NPM1 mutations (0 v 33%; P<.001), rarely had mutations in tumor suppressors (2% v 15%; P<.001) and had more RAS pathway mutations (34% v 24%; P=.04) than non-11q23/ MLL pts. NRAS and KRAS mutations accounted for 20% of total mutations in 11q23/ MLL -rearranged pts.
Analyzing each subgroup of 11q23/ MLL -rearranged pts separately, we found pts with t(9;11) had a median of 1 mutation (range: 0-6). Genes included in the RAS pathway (19%) and chromatin remodeling (17%) functional groups were most often mutated. Among specific genes, most common were NRAS mutations (11%) and tyrosine kinase domain (TKD) mutations of the FLT3 gene (11%). We did not observe NPM1 or CEBPA biallelic mutations, and only 1 pt harbored a DNMT3A mutation.
Pts with t(6;11) harbored few mutations (median: 1; range: 0-3) and had the highest frequency of RAS pathway mutations (67%; KRAS mutations were found in 47% and NRAS in 13% of pts). No pt showed a mutation in spliceosome, cohesin complex or tumor suppressor genes.
Pts with t(11;19)(q23;p13.3) or t(11;19)(q23;p13.1) had a median of 2 additional mutations (range: 0-4 mutations). Pts with t(11;19)(q23;p13.1) differed from those with t(11;19)(q23;p13.3). The latter tended to harbor more frequently NRAS mutations (29% v 7%), whereas t(11;19)(q23;p13.1) pts were observed to have more mutations in kinases (43% v 0).
Pts with t/ins(10;11) had the highest incidence of DNMT3A mutations (25%) among all 11q23/ MLL subgroups. Moreover, these pts lacked mutations in chromatin remodeling, cohesin complex or tumor suppressorgenes.
With regard to clinical outcome, the total cohort of younger AML pts with 11q23/ MLL had a 3y event-free survival (EFS) of 30%. Analyzing the different subgroups, we found that only pts with t(9;11) had a significantly better outcome than other 11q23/ MLL -rearranged pts (3y EFS, 65% v 10%; P <.001).
Conclusion: Our data revealed that pts with 11q23/ MLL -rearranged AML harbor a low number of additional mutations and lack NPM1 mutations. Yet, each specific entity showed molecular uniqueness, which makes them distinguishable. With respect to outcome, pts with t(9;11) had significantly better EFS. Our comprehensive molecular analysis using next-generation sequencing has improved the understanding of these important AML entities.
Kolitz: Gilead, Magellan, Novartis, Pharmacyclics, and Seattle Genetics: Consultancy; Boehringer Ingelheim, Cantex, Erytech, and Millennium: Research Funding; Celgene, Jazz: Equity Ownership; Gilead, Novartis, and Seattle Genetics: Other: Travel Support; Gilead, Magellan, and Novartis: Honoraria. Powell: Rafael Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stone: Jazz: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Arog: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenix: Other: DSMB; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Fujifilm: Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Astellas: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Ono: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Seattle genetics: Membership on an entity's Board of Directors or advisory committees; Sumitomo: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Byrd: Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding.
